Enhancing TCR-engineered T cell therapy with cytokine fusion proteins for pancreatic cancer treatment

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with limited responsiveness to current therapies, including immune checkpoint blockade and chimeric antigen receptor (CAR)-T cells. T cell receptor engineered (TCR)-T cells offer therapeutic potential but are rapidly rendered dysfunctional in the immunosuppressive pancreatic tumor microenvironment (TME). This project aims to enhance the persistence and antitumor efficacy of TCR-T cells in PDA through spatially-controlled expression of IL-15 cytokine fusion proteins (CFPs), which provide potent support for T cell function but are limited by systemic toxicity when delivered indiscriminately. The research has two specific aims. First, the project will define how constitutive IL-15 CFP expression augments TCR-T cell function through autocrine and paracrine mechanisms, comparing membrane-bound and secreted CFP variants and assessing their interaction with host IL-15 receptor signaling. Second, the project will develop and validate donor TCR-T cells with inducible, tumor-restricted IL-15 CFP expression using synthetic transcriptional circuits responsive to TCR activation and TGFβ signaling. These studies will be conducted using an in vitro T cell exhaustion model and in vivo adoptive cell therapy (ACT) studies in orthotopic PDA mouse models, coupled with genetic and imaging tools to assess safety, efficacy, and immune modulation. The fellowship training plan is designed to prepare the applicant for a career as an independent investigator focused on advancing T cell therapies for solid tumors. Training goals include deepening expertise in T cell biology and cancer immunotherapy, mastering technical approaches such as orthotopic tumor modeling, high- resolution imaging, and immune profiling, and developing leadership and communication skills through mentoring, manuscript preparation, and conference participation. Foundational training in bioinformatics and translational research will enhance the scope and impact of the applicant’s future work and ensure its continued relevance to clinical application. The research will be conducted in a highly collaborative and well- resourced environment at the University of Minnesota, under the mentorship of leading experts in CD8+ T cell biology, tumor immunology, and cellular engineering. This setting provides the ideal foundation for the proposed work and aligns with the broader mission of improving outcomes for patients with treatment-resistant solid tumors through innovative, mechanism-driven immunotherapies.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest cancers, with limited effective treatment options and poor responsiveness to current immunotherapies. This research aims to enhance the safety and efficacy of TCR-T cell therapy for PDA by developing tumor-restricted cytokine support strategies that overcome immunosuppression in the tumor microenvironment. In the long-term, these studies will advance the development of more effective, mechanism-driven immunotherapies for solid tumors, ultimately contributing to improved patient outcomes and reduced cancer-related mortality.